Heritability and complex segregation analysis of naturally-occurring diabetes in Australian Terrier Dogs

Mei Lun Mui; Thomas R. Famula; Paula S. Henthorn; Rebecka S. Hess

doi:10.1371/journal.pone.0239542

Peer Review History

Original SubmissionJune 30, 2020
27 Aug 2020 Decision Letter - Simon Clegg, Editor PONE-D-20-19380 Heritability and complex segregation analysis of naturally-occurring diabetes in Australian Terrier Dogs PLOS ONE Dear Prof Hess, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== Many thanks for submitting your manuscript to PLOS One Two expert reviewers were very impressed with the manuscript and have only made very minor comments for modifications If you could make the minor modifications suggested, and resubmit your manuscript with a brief response to reviewers that would aid review when resubmitted I wish to personally thank you for writing such a good paper, and making mine, and the reviewers jobs very easy. I wish you the best of luck with your revisions Hope you are keeping safe and well in these difficult times Thanks Simon ============================== Please submit your revised manuscript by Oct 11 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Simon Clegg, PhD Academic Editor PLOS ONE Journal requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Please amend the manuscript submission data (via Edit Submission) to include author Mei Lun Mui, Thomas R. Famula adn Paula S. Henthorn. 3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This manuscript evaluates the heritability of diabetes in Australian Terriers in the USA. It is well written and clearly defines the populations used and weaknesses within the study (e.g. recall bias and missing data). While the analyses incorporates less than 10% of the breed population, the authors recognise the issues associated with this small percentage of the overall population being used to provide an estimate of heritability. The authors have performed appropriate analyses of the data and present their findings clearly and concisely. They provide an estimate of heritability of diabetes in Australian Terriers in the USA, across a significant and extended multi-generation pedigree. They do not say whether this pedigree will be used to evaluate the identified genetic susceptibility region in the INS gene – which would be a valuable genetic analyses to perform for the Australian Terriers and may be of relevance to other diabetic susceptible breeds. While not part of this study, further genetic evaluation should be considered in the discussion. This manuscript will be of interest to breeders and owners of Australian Terriers and highlights the issue of diabetes within the breed. Reviewer #2: This is an excellent manuscript which examines the heritability of diabetes in Australian Terriers in the USA. It is very very well written, with clear aims and highlights some of the inherent weaknesses within the studies which is nice to see. There is also a decent number of subjects used which is again nice to see. Well written ,well analysed, and very good data collection. This is a very nice, well researched and very well written article for which the authors should be highly commended. I had great fun reading the article, and would love to see it published very soon. It is of great interest to the dog breeding and diabetes research groups, as well as the wider public. I have made a few very minor comments on the article below. But they are very minor, which highlights the excellent nature of the article. Thank you for making my life as a reviewer easy! The only comment I would say is that it would be great to see some further genetic evaluations and implications discussed but that’s about it really. Lines 41-44- these sentences could be merged to aid flow Lines 57-60 are a bit repetitive Im not sure that table 1 and 2 are adding much as they are just single line tables? These maybe better in text, but I don’t feel strongly and its up to you Line 284- does this genetic variability with diabetes also link to genetic variability of the dogs? Is there inbreeding co-efficient known for these dogs? Are there plans to use to genetic susceptibility data to prescreen animals for this disease? That would be a most useful disease diagnostic. Again- not something which needs commenting on, just a thought It would be nice to see a bit more on further genetic evaluations which maybe useful in the discussion too if you think it would be useful ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0239542.r001
Revision 1
3 Sep 2020 Author Response The authors thank the Editor and Reviewers for a concise, clear, insightful, and helpful review. All of the Reviewers’ comments have been addressed in the revised manuscript and are also listed below. Reviewer 1: 1. They do not say whether this pedigree will be used to evaluate the identified genetic susceptibility region in the INS gene – which would be a valuable genetic analyses to perform for the Australian Terriers and may be of relevance to other diabetic susceptible breeds. While not part of this study, further genetic evaluation should be considered in the discussion. The authors thank the reviewer for the suggestion. The following sentence has been added on lines 337-340 (in the revised manuscript with trach changes): “Sequencing of the 5.8 Mb insulin gene region in Australian Terriers and comparison of this sequence to that found in non-diabetic Australian Terriers holds particular promise for future genetic evaluations because this region has been associated with diabetes in this breed.” Reviewer 2: 1. Lines 41-44- these sentences could be merged to aid flow The authors thank the reviewer for the suggestion. The sentences on lines 41-43 (in the revised manuscript with trach changes) have been merged, as suggested, and now read as follows: “The Australian Terrier breed is the breed at highest risk for diabetes in Sweden, Australia, and the United States, where it is 32 times more likely to develop diabetes compared to mixed breed dogs [6, 7, 9].” 2. Lines 57-60 are a bit repetitive Thank you for the suggestion. The following sentence (now on line 64) has been deleted, as suggested: “The heritability and polygenic mode of inheritance of diabetes in Australian Terriers are reported here.” 3. Im not sure that table 1 and 2 are adding much as they are just single line tables? These maybe better in text, but I donʼt feel strongly and its up to you Thank you for the suggestions. Table 1 has been deleted and replaced with the following sentence on lines 219-221: “Heritability of diabetes risk in Australian Terrier dogs in a mixed logistic regression model was estimated as 0.18 (95% posterior interval 0.00-0.67).” Table 2 was also deleted and its contents were incorporated into the following sentence on lines 222-224: “There was no significant difference in the sex effect on the risk of diabetes detected in the mixed logistic regression model (0.37, 95% posterior interval -0.23-0.94).” 4. Line 284- does this genetic variability with diabetes also link to genetic variability of the dogs? Is there inbreeding co-efficient known for these dogs? Thank you for the query. The following sentence has been added to what is now lines 309-313, as suggested: “Making use of the available pedigree, all known relationships (including any inbreeding) were incorporated into the estimated heritability. Provided the pedigree in this study is a representative subset of all Australian Terriers, any impact of the presence of this inbreeding on our estimates would be expected to be negligible.” 5. Are there plans to use to genetic susceptibility data to prescreen animals for this disease? That would be a most useful disease diagnostic. Again- not something which needs commenting on, just a thought The following sentence has been added to lines 313-315, as suggested: “The data generated here could also be used to calculate estimated breeding values of diabetes in US Australian Terriers, to help guide future breeding and decrease the risk of diabetes in this breed.” 6. It would be nice to see a bit more on further genetic evaluations which maybe useful in the discussion too if you think it would be useful The following sentence has been added on lines 337-340: “Sequencing of the 5.8 Mb insulin gene region in Australian Terriers and comparison of this sequence to that found in non-diabetic Australian Terriers holds particular promise for future genetic evaluations because this region has been associated with diabetes in this breed.” Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0239542.r002
9 Sep 2020 Decision Letter - Simon Clegg, Editor Heritability and complex segregation analysis of naturally-occurring diabetes in Australian Terrier Dogs PONE-D-20-19380R1 Dear Prof. Hess We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Simon Clegg, PhD Academic Editor PLOS ONE Additional Editor Comments: Many thanks for resubmitting your manuscript to PLOS One As all the comments have been addressed, I have recommended your manuscript for publication You should hear from the Editorial Office shortly It was a pleasure working with you, and I wish you all the best for the future Hope you are keeping safe and well in these difficult times thanks Simon https://doi.org/10.1371/journal.pone.0239542.r003
Formally Accepted
14 Sep 2020 Acceptance Letter - Simon Clegg, Editor PONE-D-20-19380R1 Heritability and complex segregation analysis of naturally-occurring diabetes in Australian Terrier Dogs Dear Dr. Hess: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Simon Clegg Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0239542.r004

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